Modulation of Membrane Lipid Receptors Explored via Multiscale Computer Simulations
Research output: Book/Report › Doctoral thesis › Collection of Articles
|Publisher||Tampere University of Technology|
|Number of pages||92|
|Publication status||Published - 13 Dec 2018|
|Publication type||G5 Doctoral dissertation (article)|
|Name||Tampere University of Technology. Publication|
In the ﬁrst part of this Thesis, the functional properties of PI(4,5)P2 were studied through lipid–protein interactions between PI(4,5)P2, talin, and integrin. The simulations revealed a new means on how PI(4,5)P2 together with talin interferes with the stability of the integrin transmembrane domains, suggesting a new mechanism for the ﬁrst steps of integrin activation.
The second part of this Thesis focuses on various mechanisms that can alter and regulate lipid receptor binding properties. First, the binding of cholera toxin to GM1 and the ﬂuorescent analog of the receptor was examined. A clear diﬀerence in the behavior between the native and the labeled GM1 was observed. These results highlight the importance of artifacts that ﬂuorescent labeling can cause. Second, the intracellular calcium was shown to aﬀect the PI(4,5)P2 headgroup tilting and the related ligand binding. Importantly, these results were directly linked to cell signaling events through experimental ﬁndings observed by our collaborators. Finally, the fundamental question as to how the PI(4,5)P2 receptor is recognized only in the plasma membrane but not in the other cell compartments was explored. Enhanced ligand binding to cholesterol-rich PI(4,5)P2 membranes was found, suggesting that the steep cholesterol gradient along the secretory pathway in a cell may be a part of the machinery coordinating the speciﬁc cell organelle recognition.
Altogether, the Thesis provides novel insight on the function of lipid receptors, modulation of lipid–protein interactions, and highlights the added value gained by bridging scientiﬁc computing and novel computing tools with experimental science.